Transcranial brain stimulation

ABSTRACT

An apparatus and method for transcranial magnetic brain stimulation. The apparatus allows transcranial stimulation at higher power efficiency and lower heat generation than prior available magnetic stimulator coils without an iron core. Use of the apparatus allows an improved method for active localization of language function. The device can also be used in rapid rate transcranial magnetic stimulation for the treatment of depression.

RELATED APPLICATIONS

This application claims the priority of PCT Application Ser. No.PCT/US97/14826, filed Aug. 15, 1997, which claims priority of U.S.Provisional Application Ser. No. 60/023,421, filed Aug. 15, 1996, and isa continuation-in-part of U.S. patent application Ser. No. 08/345,572,filed Nov. 28, 1994 now U.S. Pat. No. 5,725,471, the disclosures ofwhich are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to an apparatus for transcranial magneticbrain stimulation. The invention also relates to methods for localizingand characterizing speech arrest, and for treatment of depression usingtranscranial magnetic stimulation.

BACKGROUND OF THE INVENTION

The Magnetic Stimulator Apparatus

Magnetic stimulation of neurons has been heavily investigated over thelast decade. Almost all magnetic stimulation work has been done in vivo.The bulk of the magnetic stimulation work has been in the area of brainstimulation.

Cohen has been a rather large contributor to this field of research (Seee.g., T. Kujirai, M. Sato, J. Rothwell, and L. G. Cohen, "The Effects ofTranscranial Magnetic Stimulation on Median Nerve Somatosensory EvokedPotentials", Journal of Clinical Neurophysiology and ElectroEncephalography, Vol. 89, No. 4, 1993, pps. 227-234, the disclosure ofwhich is fully incorporated herein by reference.) This work has beenaccompanied by various other research efforts including that of Davey,et al. and that of Epstein (See, K. R. Davey, C. H. Cheng, C. M. Epstein"An Alloy--Core Electromagnet for Transcranial Brain Stimulation",Journal of Clinical Neurophysiology, Volume 6, Number 4, 1989; and,Charles Epstein, Daniel Schwartzberg, Kent Davey, and David Sudderth,"Localizing the Site of Magnetic Brain Stimulation in Humans",Neurology, Volume 40, April 1990, pps. 666-670, the disclosures of whichare fully incorporated herein by reference).

Generally, the magnetic stimulation research has used air type coils intheir stimulators. These coils are so named due to the fact that theylack a magnetic core. A well known producer of such coils is Cadwell,which produces a variety of different models. One of the goals of thepresent inventors has been to provide magnetic stimulator devices foruse in a variety of applications, which are improvements over thedevices previously used in the art. In our prior pending patentapplication, U.S. patent application Ser. No. 08/345,572, filed Nov. 28,1994, which is the parent to the present application (the disclosure ofwhich is fully incorporated herein by reference), a variety of suchdevices were disclosed for the use in peripheral nerve stimulation.Accordingly, it is an object of the present inventors herein to providefurther devices for use in central nervous system stimulation ingeneral, and transcranial brain stimulation in particular.

The Treatment of Depression

Transcranial magnetic stimulation is known to non-invasively alter thefunction of the cerebral cortex. (See e.g., George M S, Wassermann E M,Post R M, Transcranial magnetic stimulation: A neuropsychiatric tool forthe 21st century, J. Neuropsychiatry, 1996; 8: 373-382, the disclosureof which is fully incorporated herein by reference). The magnetic fieldsused are generally generated by large, rapidly-changing currents passingthrough a wire coil on the scalp. Two recent studies have suggested thatrapid rate transcranial magnetic stimulation (rTMS) may be used forexploring the functional neuroanatomy of emotions: healthy volunteerswho received left pre-frontal stimulation reported an increase inself-rated sadness, while, in contrast, right pre-frontal stimulationcaused an increase in happiness. (See, Pascual-Leone A., Catala M D,Pascual A P, Lateralized effect of rapid rate transcranial magneticstimulation of the prefrontal cortex on mood, Neurology, 1996; 46:499-502; and, George M S, Wasserman E M, Williams W., et al., Changes inmood and hormone levels after rapid-rate transcranial magneticstimulation of the prefrontal cortex, J. Neuropsychiatry Clin. Neurosci.1996; 8: 172-180, the disclosures of which are fully incorporated hereinby reference.)

Other reports have begun to delineate the therapeutic use of rTMS indepression. The earliest such studies used round, non-focal coilscentered at the cranial vertex, with stimulation rates well under 1Hertz (Hz). Results were promising but not always statisticallysignificant. (See, Hoflich G., Kasper S. Hufnagel A. et al., Applicationof transcranial magnetic stimulation in treatment of drug-resistantmajor depression: a report of two cases, Human Psychopharmacology, 1993;8: 361-365; Grisaru N., Yarovslavsky U., Abarbanel J., et al.,Transcranial magnetic stimulation in depression and schizophrenia, Eur.Neuropsychophannacol. 1994; 4: 287-288; and, Kilbinger H M, Hofllich G.,Hufnagel A., et al., Transcranial magnetic stimulation (TMS) in thetreatment of major depression: A pilot study, Human Psychopharmacology,1995; 10: 305-310, the disclosures of which are fully incorporatedherein by reference.)

Subsequently, George et al., described striking improvement in somedepressed patients from treatment with rTMS over the left pre-frontalcortex. (See, George M S, Wasserman E M, Williams W A, et al., Dailyrepetitive transcranial magnetic stimulation (rTMS) improves mood indepression, NeuroReport, 1995; 6: 1853-1856; and, George M S, WassermanE M, Williams W E, Kimbrell T A, Little J T, Hallett M., Post R M, Dailyleft prefrontal rTMS improves mood in outpatient depression: a doubleblind placebo-controlled crossover trial, Am. J. Psychaitry, 1997 (inpress), the disclosures of which are fully incorporated herein byreference). The largest such study to date was reported by Pascual-Leoneet al., who used a five-month double blind placebo-controlled cross overdesign with five different treatment conditions. (See, Pascual-Leone A.,Rubio B., Pallardo F. Catala M D, Rapid-rate transcranial magneticstimulation of left dorsolateral prefrontal cortex in drug-resistantdepression, The Lancet, 1996; 348: 233-237, the disclosure of which isfully incorporated herein by reference.) Left pre-frontal rTMS wasuniquely effective in 11 of 17 young (less than 60 years of age)psychotically depressed and medication resistant patients.

Accordingly, further to the work which has been done thus far in thisfield, it is also a goal of the present inventors to provide improvedapparatus and methods for transcranial magnetic stimulation, and for thetreatment of depression using such stimulation, as described more fullyhereafter.

The Localization of Speech Arrest

With respect to the methods previously used for the localization ofspeech arrest, active localization of language function hastraditionally been possible only with invasive procedures. The dominanthemisphere can be determined using the intracarotid amobarbital or Wadatest. Cortical areas critical to language can be mapped usingelectrocorticography in the operating room, (See e.g. Penfield, 1950,cited below) or extra-operatively through electrode grids implanted inthe subdural space. (See e.g. Lesser, 1987, cited below). The Wada testand electrocorticography have contributed greatly to our currentunderstanding of language organization. However, because of theircomplexity and potential morbidity, these techniques are confined almostentirely to patients undergoing surgery for intractable epilepsy.

In the past decade, positron emission tomography and functional magneticresonance imaging have shown promising results for languagelocalization. But these newer imaging technologies requite complex andexpensive equipment, and have other limitations in the form of poortemporal resolution or a restricted test environment. The correlationbetween the degree of metabolic change in different brain areas andtheir importance for a given cognitive task remains unknown. (See e.g.,Ojemann, cited below).

At least four groups have reported lateralized speech arrest usingrapid-rate transcranial magnetic brain stimulation (rTMS) in epilepsypatients. (See e.g., Pascual-Leone, 1991, Michelucci, 1994, Jennum,1994, and Epstein, 1996, cited below). The results showed a highcorrelation with the Wada test, but sensitivity in the two largestseries was only 50-67% (See, e.g., Jennum, 1994, and Michelucci, 1994,cited below). Most of these studies used large circular magnetic coils,along with stimulus parameters that may carry a risk of inducingseizures. (See, e.g. Pascual-Leone, 1993, cited below). Thus, theinitial rTMS techniques were not optimal for detailed localization orfor studies involving normal subjects.

Consequently, further to the work which has previously been done, it isalso a goal of the present inventors to provide improved apparatus andmethods for localization and characterization of brain function. Asdescribed hereafter, we recently described modifications of rTMS thatproduce lateralized speech arrest with reduced discomfort, a repetitionrate as low as four Hertz, and a combination of stimulus parameters thatcomply with recent recommendations for safety in rTMS (See also, EpsteinC M, Lah J J, Meador K, Weissman J D, Gaitain L E, Dihenia B, Optimumstimulus parameters for lateralized suppression of speech with magneticbrain stimulation, Neurology, 47: 1590-1593 (December 1996), thedisclosure of which is fully incorporated herein by reference). Thetechnique is useful for detailed studies of magnetic speech arrest innormal individuals.

SUMMARY OF THE INVENTION

An object of the present invention is to provide an improved apparatusfor transcranial magnetic brain stimulation.

A further object of the present invention is to provide an improvedmethod for characterizing and localizing brain function.

A further object of the present invention is to provide an improvedmethod for characterizing and localizing speech arrest.

A further object of the present invention is to provide an improvedmethod for treatment of depression.

As disclosed more fully hereafter, an apparatus is described for use intranscranial brain stimulation. The apparatus is designed to produce afocussed magnetic field which can be directed at sites on the brain ofinterest or importance. The device consists of at least one, butpreferably four magnetic cores. The cores are preferably constructed ofa ferromagnetic material. The cores can have an outer diameter betweenapproximately 2 and 7 inches, and an inner diameter betweenapproximately 0.2 and 1.5 inches. The material of the cores has amagnetic saturation of at least 0.5 Tesla, and preferably at least 1.5Tesla, or even 2.0 Tesla or higher. In the preferred embodiment, thecore conforms in construction to the shape of the head to improve itsefficacy. A visualization and location port is included to assist withthe precision placement of the core on the head, and to assist withexact marking of the stimulator's position.

Using the described apparatus and method, an optimized technique fortranscranial magnetic brain stimulation is provided which has a varietyof useful applications. For example, the present apparatus and methodcan be employed for brain stimulation in a therapeutic protocol for thetreatment of depression. In addition, the apparatus and method can beused for the localization and characterization of brain function. Forexample, detailed anatomic localization of speech arrest and effects onother language function can be studied. The invention therefore providesdevices and methods for non-invasive stimulation and treatment of thebrain, and for studying and characterizing brain function, which areimprovements over the procedures of the prior art.

Using the apparatus and technique on four normal righthanded volunteers,to study speech arrest for example, it was determined that all weredominant for magnetic speech arrest over the left hemisphere. Whilesubjects counted aloud, points of speech arrest were mapped on aone-centimeter grid over the left frontal region. Compound motor actionpotentials from muscles in the right face and hand were mapped onto thesame grid. Subjects were then tested in reading, writing, comprehension,repetition, naming, spontaneous singing, and oral praxis during magneticstimulation. Finally, mean positions for speech arrest and muscleactivation were identified on three dimensional MRI.

All of the subjects tested using the present technique had complete,lateralized arrest of counting and reading with magnet stimulation overthe left posterior-inferior frontal region. Writing with the dominanthand, comprehension, repetition, visual confrontation naming, oralpraxis, and singing were relatively or entirely spared, with rareaphasic errors. In two subjects, melody was abolished from singingduring stimulation over the right hemisphere. In all four subjects, theregion of speech arrest was highly congruous with the region wherestimulation produced movement of the right face, and overlay the caudalportion of the precentral gyrus. This constellation of behavioral andanatomic findings is similar to that found in aphemia, and supports amodular theory of language organization in the left hemisphere.

In patients with refractory depression, the stimulator of the presentinvention was used to stimulate the brain with magnetic pulses usingrapid rate transcranial magnetic stimulation over the left prefrontalregion of the brain. In a group of 32 patients aged 22-64, all HamiltonDepression (Ham-D) scores were above 20 prior to treatment. Twenty-eight(28) patients completed treatment: average Ham-D scores fell from thirtyone (31) to fifteen (15), and individual scores fell to less than ten(10) in fourteen (14) out of twenty-eight (28) of the subjects. Sixteen(16) out of the twenty eight (28) patients were clear responders torTMS. Two enrollees dropped out because of pain during stimulation, andthree had possible adverse effects during the course of treatment thatwe were unable to connect causally with rTMS. Thus, it was found thatrTMS could be used as a simple and effective treatment for many patientswith refractory depression who would otherwise be candidates for ECT.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a top view of a transcranial magnetic brain stimulator inaccordance with the present invention while FIG. 1A is a side viewthereof.

FIG. 2 is a top view of a second embodiment of a transcranial magneticbrain stimulator in accordance with the present invention with FIG. 2Abeing a side view thereof.

FIG. 3 is a front view of a transcranial magnetic brain stimulatorformed from 4 cores in accordance with FIGS. 1 or 2, as positioned on aschematic human head.

FIG. 4 is a side view of the stimulator of FIG. 3 on a schematic humanhead.

FIG. 5 presents a series of three tables showing experimental resultsfrom the use of the present stimulators for the treatment of depression.Table 1 shows the antidepressant dosages of indicated medicationreceived by experimental subjects prior to rTMS. Table 2 shows the agesand sex of the responders and non-responders to treatment. Table 3 showsthe diagnoses of the responders and non-responders to treatment.

FIG. 6 is a histogram of the differences between post-treatment andpre-treatment Hamilton Depression scores for all patients completing acourse of rTMS.

FIG. 7 is a graph showing comparative results for use of the presentstimulator in comparison to several other devices.

FIG. 8 shows the components used to form a third embodiment of atranscranial magnetic brain stimulator in accordance with the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTS

The Magnetic Brain Stimulator

To accomplish the magnetic stimulation described in the presentapplication, an improved apparatus for transcranial magnetic brainstimulation is disclosed herein, as further set forth below and in theaccompanying drawings. The design of the apparatus is related to thedesigns previously described in U.S. patent application Ser. No.08/345,572 filed Nov. 28, 1994 (pending), the disclosure of which isfully incorporated herein by reference, and upon which the presentapplication claims priority. Diagrams of the novel magnetic stimulatorare provided in FIGS. 1-3. The specifications and details of thecomponents of the stimulator are shown therein. The devices of thepresent invention induce electric fields similar in distribution tothose from a Cadwell water-cooled figure-eight coil. However, thepresent inventions are much smaller, quieter, and more efficient,requiring no special cooling.

As shown in FIGS. 1 and 2, a core for a magnetic nerve stimulator isprovided for stimulation of the brain. The stimulator core 27 is made ofa magnetic material, preferably a ferromagnetic material. In thepreferred embodiments, the material of the core has a magneticsaturability of at least 0.5 Tesla. Higher saturabilities are preferred,however, with saturabilities of at least 1.5 Tesla or higher, or even2.0 Tesla or higher recommended in the preferred embodiments. Preferredmaterials for the core include vanadium permendur or 3% grain orientedsteel.

As shown in FIG. 1, in the preferred embodiment, core 27 is cut from anoval winding of 2 mil vanadium permendur. Two cores can, in fact, be cutfrom a single oval winding, by cutting one core from each side of theoval. For illustration purposes, only a single core is shown in thediagram of FIG. 1.

The method of construction of such a core is as described previously inour patent application, which is the parent to the present application,U.S. application Ser. No. 08/345,572, filed Nov. 28, 1994. The bestcores are constructed from thin laminate, highly saturable material(i.e. materials with a saturability of at least 1.5-2.0 Tesla, althoughless saturable materials with a saturability of 0.5 Tesla and higher canbe used as well).

A typical core can be wound using two mil stock of vanadium permendur. Along ribbon of such material is wound on a mandrel (e.g. a mandrel ofwood or plastic) for the radius, thickness and depth desired. Each sideof the ribbon is coated with a thin insulative coating to electricallyisolate it from its neighbor. After cutting the core from the entireoval winding, a suitable core might span an angle of approximately 208°,or in the range of about 205-215°, as shown in FIGS. 1, 2 and 8. Otherangles are possible, as well, however, though not preferred, asdescribed below.

Once the ribbon has been wound on the mandrel to the desired dimensions,it is dipped in epoxy to freeze its position. Once the epoxy has dried,the mandrel is removed and the core may be cut for the span of angledesired. The cut may destroy the electrical isolation of adjacentlaminations. Each cut must be finely ground so that it is smooth, andthen a deep etch performed. The deep etch is performed by dipping eachof the cut ends in an acid bath. This causes the cut ends to delaminateslightly, but maintains the electrical isolation of the laminations.Failure to perform this deep etch seems to result in considerable eddycurrent loss and heating at the cut ends of the core. Following the deepetch, the ends are brushed with epoxy to maintain the shape andstructural integrity of the core. The final step of the construction isto wind a coil of insulated wire about the core. A typical inductancefor a core of this type is about 20 μH. The present invention, however,may be practiced at other inductances or magnetic field strengths, ifdesired.

As an alternative to cutting the core as one entire section, the corecan be cut as a semi-circular section. In this method of manufacture,the small triangular sections 34 at the bottom of the core are then cutseparately, and attached to the semi-circular section as shown in theFigures. Preferably, the smaller triangles are also made from vanadiumpermendur. If necessary, however, the triangles can be any material oralloy that has a saturation of at least 0.5 Tesla, and which can beworked by one of ordinary skill in the art. A suitable alloy for thetriangular sections, for example, is 2 mil 50% nickel alloy.

As shown in FIG. 1, in the preferred embodiment, core 27 has an outerdiameter of approximately 4.75 inches. The core 27 has an innersemi-circular aperture 38 at the center of the core 27. Inner semicircle38 has a diameter of approximately 0.75 inches. In a version where thesmaller triangles are separate, triangular sections or wedges 34 areattached to the larger semi-circular section. Triangular sections 34have a length on longer side 40, in contact with semi-circular section30, of approximately 1.375 inches, and a length of approximately 0.75inches on shorter side 42 which is approximately coplanar with theoutside of semi-circular section 30. As shown in FIG. 1A, the crosssectional width of core 27 is approximately 0.625 inches.

A second version of the core is shown in FIG. 2. Core 51 is merely asmaller version of the core 27 shown in FIG. 1. Core 51 has a outerdiameter of 3.75 inches, and an inner diameter 56 of approximately 0.875inches. The triangular sections 54 attached to the ends of thesemicircular core have a length of approximately 0.47 inches on shorterside 116 and a length of approximately 0.875 inches on longer side 114.As mentioned with respect to FIG. 1, the cores are preferably cut suchthat the triangular sections 54 are an integral part of the core 51,however, the triangular sections 54 can be cut separately and attachedto a semi-circular section of core, if necessary or desired. In thepreferred embodiment, the core with triangular sections subtends anangle of approximately 208 or 205-215 degrees as measured from thecenter of inner diameter 56 to the far edge of shorter side 116. Thisembodiment shows the core as having a thickness of about 0.5" (FIG. 2A).

A third embodiment of the core is shown in FIG. 8. In this embodiment,two separate layers of materials are used. An inner layer 74 is providedwhich is constructed of 2 mil vanadium permendur. Outer layer 79 isconstructed of 2 mil 50% nickel alloy. The preferred dimensions of therespective layers are as follows: inner diameter 140 of inner layer 74is preferably 0.875 inches, and outer diameter 142 of inner layer 74 ispreferably 2.625 inches. The inner diameter of outer layer 79 is thesame as the outer diameter of inner layer 74. Outer diameter 144 ofouter layer 79 is preferably 4.375 inches. The horizontal dotted lineindicates where the semi-circular portion of the winding ends and thetriangular pieces begin. The short side of inner triangle 146 ispreferably 0.21875 inches, and the short side of outer triangle 148 ispreferably 0.6875 inches. The overall thickness of the embodiment ispreferably 0.625 inches. The inner and outer ovals are wound andseparately cut. A single oval can be used to cut two inner cores, and asecond oval can be used to cut two outer cores. The inner layer 74 andthe outer layer 79 are then nested together as shown in FIG. 8.

As shown in the Figures, each of the cores of the stimulator ispreferably an open core, i.e. the core forms an open arc, and does notconstitute a closed toroid. An approximately C-shaped core ispreferable. In accordance with the present design, at least a portion ofthe core of the stimulator conforms, at least approximately, to theshape of the head. In the preferred embodiment, a hemisphericalstimulator, having at least one, but preferably four adjacent, cores(see FIG. 3) made of saturable or highly saturable ferromagneticmaterial, is used, as shown in the Figures.

The span of the core affects both the penetration depth of the magneticfield and the magnitude of the field. While a variety of angles areacceptable for the curvature of the arc of the core, a core of 208degrees or approximately in the range of about 205-215 degrees is shownin the Figures for preferred embodiments. In other embodiments, cores ofapproximately 190-230 degrees can be utilized. Alternatively, a corespanning an arc of approximately 180-270 degrees is also possible,although not necessarily as effective.

In the preferred embodiment, to form the stimulator, four cores arepositioned approximately side by side to form a complete magneticstimulator. Although more than four cores or less than four cores arepossible, four are preferred. As shown in FIGS. 3 and 4, two pairs ofcores are placed side by side to form a hemisphere designed forplacement on the head. The combined cores are wound with a series ofwindings of wire. In the preferred embodiment, approximately nine to tenturns of wire are used; approximately nine (9) turns of wire beingpreferably wound around the larger stimulator formed of cores of FIG. 1,and approximately ten (10) turns of wire being wound around the smallerstimulator formed of cores of FIG. 2. As shown in FIGS. 3 and 4,approximately four-five (4-5) turns of wires are wound around each halfof the stimulator, i.e., approximately four to five turns are woundaround a first side of the stimulator, and another four to five turnsare wound around the second side of the stimulator.

In accordance with the present invention, it is also preferred that thestimulator be provided with a visualization and location port forviewing and marking the head and locating the stimulator thereon. In thepresent invention, a space is left open between the two pairs of coresto form a center port 62 (see FIG. 3). Center port 62 extends from thetop of the stimulator down to the surface of the patient's head as shownin FIG. 3. It is preferred that a length of plastic or copper tubing beinserted in this area to form the port. Port 62 is of sufficiently largediameter that a marking device such as a pen or felt marker can beinserted into the port 62 through the stimulator to mark the head'ssurface (or to mark a cap worn on the head). Thus, as an illustration ofthe construction of the port 62, the internal ink containing cylindercan be removed from a standard writing device, such as a Papermate™ pen,leaving the pen's outer plastic section of tubing empty. This outerplastic section of tubing can be inserted between the two pairs of coresto serve as the tubing for the port. The internal, ink containingportion of the pen can later be inserted down and through this port tomark the patient's head. Any suitable tubing and any marker of smallerdiameter than the tubing, can of course, be used, and the presentexample is not meant as a limitation.

Port 62 has importance both as a means to precisely mark where astimulator is located on the head, and as a means to precisely positionthe stimulator. When the stimulator is placed on the head, the markingdevice or pen can be inserted down the port and through the stimulatorto make a mark on the head of the patient. The mark serves as aneffective reference, indicating exactly where the stimulator waspositioned. This provides a convenient and effective means of preciselyrecording the stimulator location for later reference.

Likewise, if it is desired that the stimulator be centered over aparticular region of the head a mark can first be placed on the head inthe appropriate area. Or, if it is desired that the stimulator be placedon the same location in successive sessions, an appropriate mark can beleft on the head after the first positioning. In either situation, byviewing down the port of the stimulator, the stimulator can be movedaround over the head until the marked area is within view through theport, so that the stimulator can be positioned on the exact locationdesired.

FIG. 7 shows a comparison of several coils at 30% output, measured inair. At the critical depth of two cm below the coil, the presentferromagnetic core system, as disclosed herein, induces approximatelytwice the electric field of an oversized plain coil, and more than twicethat of a standard commercial coil from Cadwell. The power improvementis the square of this ratio.

Thus, in the present design, the semi-circular configuration optimallycombines with a double-loop wire coil, and the concave active surfacedelivers maximal magnetic flux to the brain and other physiologicaltargets. Of the large number of other magnetic stimulators that havebeen developed or are in use, the present inventors are not aware of anyother design having comparable advantages or performance. In the presentdevice, focal magnetic stimulation is provided with an approximatetwofold amp-turn efficiency and 1/4th the heat generation of prioravailable stimulation coils without a ferromagnetic core. Triangularextensions and curvature of the active surface significantly improveefficiency of brain stimulation. The device allows more powerful andfocused stimulation than any existing alternative, and, alternatively,allows conventional stimulation at a much lower energy cost. It uniquelyallows continuous high speed magnetic stimulation without requiringspecial provisions for cooling. Moreover, projection of the magneticfield into the brain is effective even when the core is partiallysaturated.

In the preferred embodiment of the present invention, the electricalcircuitry and parameter referred to in co-pending application Ser. No.08/345,572 filed Nov. 28, 1994 are employed with the stimulator taughtherein. Alternatively, any other suitable circuit and power source canbe used, as well be apparent to those of ordinary skills in the art.

Magnetic Brain Stimulation for Localization of Language Function

Among the many suitable applications of this device, the presentinventions may be used to provide an improved technique for activelocalization and characterization of brain function. In one particularembodiment, it is possible to locate and characterize language function.This technique was tested on four subjects, all being right-handed malephysicians, ages 31-49, studied under informed consent. All hadpreviously shown dominance for magnetic speech arrest over the lefthemisphere. (See, e.g., Epstein, 1996, cited below)

For magnetic mapping, the subjects were seated comfortably andunrestrained. The head was covered with a thin latex swim cap, whichsimplified position measurements over a large scalp area that includedup to 100 possible sites of stimulation. Any redundant latex folds weretaped down, and the position of the cap was labeled using as landmarksthe inion, distance from nasion, earlobes, and vertex. One-centimetergrid lines were drawn over the posterior frontal region and labelledalpha-numerically. Relaxed motor threshold was determined as previouslydescribed, (See Epstein, 1996, cited below) using the dominant firstdorsal interosseous (FDI) or abductor pollicis brevis (APB) to representthe hand. With this technique, threshold is defined as the lowestintensity of stimulation that produces compound motor action potentials(CMAPs) of 50 μV or greater on five of ten trials; (See, e.g.Pascual-Leone, 1993, cited below) consequently averaged CMAPs areexpected to be non-zero at threshold.

Mapping of CMAPs from FDI or APE was performed using the disclosedferromagnetic core (vanadium permendur) stimulation coil, with theinduced electric field maximum beneath the center point of the device. Asmall port through the middle allows precise marking and positioning.The coil was placed so that the induced electric field was alignedhorizontally--that is, along a sagittal or axial plane. With the righthand relaxed, we averaged eight responses to left hemisphere stimulationat a rate of 1 Hz. Testing was extended in all directions on the griduntil a 2-cm rim of absent responses completely surrounded the area ofactivation. Mapping was done in the same manner from the rightorbicularis oris (ORO) in all subjects, but facilitation was used if noresponse could be obtained during relaxation at stimulator outputs up to20% greater than hand motor threshold.

Speech interruption was tested with the same coil while the subjectcounted briskly and repetitively upward from one to 20. The stimulatorwas activated at a rate of four Hertz about the time the count reachedthe number "five." Stimulator output was adjusted differently in thefour subjects, from a level that barely produced complete speech arrestto intensities 5-10% higher. The degree of speech interruption was ratedby both subject and observers as complete, moderate, slight, or absent.

In a separate session, the stimulation coil was repositioned over thearea of maximum speech arrest. After obtaining appropriate baselines,the following tasks were carried out during stimulus trains of 3-5seconds duration:

reading unfamiliar material aloud;

reading silently and then describing content;

spontaneously describing the events of the "cookie theft picture";

hearing and obeying two-step commands with inverted syntax;

visual confrontation naming, using slide projections of 14 familiarobjects;

writing numbers from "one" upward;

repetition of two brief phrases, including "no ifs, ands, or buts";

singing lyrics to a familiar song;

tests of oral praxis, including tapping the upper teeth with the tongue,licking the lips from side-to-side, and alternating lip puckering andblowing.

Writing and visual confrontation naming were then repeated with thestimulator placed 2 cm anterior to the position of maximum speecharrest. Singing was repeated during stimulation of the homologous areaover the right hemisphere. A delay of ten seconds or more was alwayspresent between stimulus trains.

For construction of a two-dimensional map, the average CMAPsrepresenting each muscle were scaled to a maximum of one. Completespeech arrest was arbitrarily assigned a magnitude of 1.0, moderatespeech interruption 0.5, and slight speech interruption 0.25. Bubblecharts were plotted with the area of each bubble corresponding to themagnitude of the response at that site. For each muscle and for speecharrest, a two dimensional mean position on the grid was calculated.These positions were marked on the swim cap, which was then replaced onthe subject's head and realigned to the previous anatomic landmarks.Each center of gravity was marked with a capsule of vitamin E foridentification on MRI. Cranial MRI was then performed.

Measurement of the induced electric field was performed in a spherical,saline filled model head of radius 7.5 cm, using a differential probewith silver-silver chloride electrodes as previously described. (SeeEpstein, 1996, cited below). This was followed by three dimensionalreconstruction of the MRIs.

In this test of the invention, complete speech arrest was obtained overthe left posterior-lateral frontal lobe during counting and readingaloud in all four subjects. In three subjects counting and reading wereentirely normal on right-sided stimulation at the same intensity. Theother subject had slight dysarthria with stimulation on the right.Remarkably, visual confrontation naming was intact for most objects inall subjects, with variable slowing of responses and slight dysarthria.Rare aphasic errors usually consisted of word substitutions. Writingnumerals was intact in the right hand at both left frontal sites ofsimulation, even though one subject had slight jerking of the rightupper extremity. The other three subjects underwent a second writingtest in which they spelled out the numbers, again with no difficulty.Singing was consistently easier than spontaneous speech, with slight tomoderate slowing or dysarthria but with preservation of melody. However,in two of three subjects so tested, stimulation over the righthemisphere produced flattening and loss of melody that was apparent toboth the subject and the observers, This effect was obtained in onesubject as the same intensity used for speech arrest, and in the otheronly at a setting 10% higher.

Resting motor maps were easily constructed for the hand using FDI inthree subjects and APB in one. Only two subjects had facial CMAPsobtainable from the ORO at rest. The other two maps of ORO were obtainedwith facilitation: one subject gently pursed his lips, while the othercounted aloud during averaging of CMAPs.

In one series of tests, speech arrest was tested at a relatively lowintensity, equal to 95% of resting threshold in FDI. In another seriesof tests, speech was tested at a higher relative intensity of 118%, andfacilitation was not necessary for recording of facial CMAPs. But theuse of different hand muscles and different kinds of facilitation forORO had little effect on the relative map positions. The area ofstimulation that produced speech arrest was always congruous with thearea which gave motor responses from ORO. In the coronal plane, thecenter of gravity for SA lay an average of 0.5 cm from that for ORO. Inthe axial plane, the center of gravity for SA lay, on average, 0.7 cmposterior to that for ORO.

The smallest rectangle of the mapping grid that encloses the sites ofspeech arrest can be described as the "local area." Within the localarea, the first two subjects showed no correlation between the degree ofspeech arrest and the magnitude of facial muscle contraction. Asignificant correlation was found for subjects 3 and 4, in the latterthe level of stimulation was relatively high during language mapping.Thus, the congruence for speech arrest and facial movement was notconsistently present on a detailed level.

Through our studies it has therefore been found that magneticstimulation of the dominant hemisphere produces specific impairments oflanguage output, and not simply anarthria: some modalities of speech areaffected profoundly, but others minimally or not at all. Magneticinterference most affects spontaneous speech. It has less effect onrepetition, confrontation naming, and singing, while writing is entirelyspared. Magnetic speech arrest is not Broca's aphasia. The site ofaction is congruous with the region of facial motor responses, ratherthan anterior to the motor strip as might be expected from classicmodels of language organization.

During neurosurgical mapping procedures, with direct electricalstimulation of the cortex, speech arrest can be obtained over extensiveareas of both hemispheres. The most frequent site is the facial portionof the primary motor area, near the junction of the Sylvian and Rolandicfissures. (See, e.g. Penfield, 1950 and Ojemann, cited below) This isthe same region implicated in magnetic speech arrest over the dominanthemisphere. In contrast with electrocorticography, however, magneticstimulation produces speech arrest in only one location, and has littleeffect on confrontation naming in this area or anterior to it.

Many features of magnetic speech arrest are similar to those of thearticulatory disorders variously described as pure motor aphasia, pureanarthria, cortical dysarthria, simple aphasia, phonetic disintegration,and aphemia. Such cases have been described with subcortical lesions ofthe lateral frontal region, but when cortical lesions are responsiblethey are found in the lower motor strip and Rolandic operculum. Clinicalfindings include marked slowing of speech output, stuttering,preservation of grammar, and relative preservation of repetition andsinging. Writing is generally spared. Many authors, including PierreMarie, distinguish a pure articulatory disturbance from aphasia on thebases of intact comprehension, reading, and writing. (See, e.g. Marieand Schiff, cited below) Others have noted the frequent association withlexical errors (Kaminski) and other forms of language disorganization,and prefer to classify aphemia as a limited form of aphasia (L&L).

The function most impaired by magnetic stimulation is the de novoassembly of spontaneous speech and the complete arrest of languageoutput by stimulation races as low as two per second is a strikingfeature. The rapid, precise, coordinated synthesis of multiplelingual-buccal-vocal movements into consecutive phonemes represents oneof the most extraordinary tasks carried out by the human motor system,and it's reasonable to hypothesize that a specialized language modulemay be dedicated to it. Such a module would be tightly interwoven withthe primary motor cortex; as a final common pathway it might be moredifficult to bypass with parallel pathways of language processing.Magnetic interference with speech may be lessened when the constructionof phonemes is cued by speech reception, melody, or the presentation offamiliar visual objects. This amelioration of the deficit by otherneural inputs stands in distinction to aphemia and also to the classicalaphasias, all of which are characterized by impairment of repetition.

Functional maps of the type used here have important limitations,including the relatively large area and elliptical shape of the inducedelectric field. This shape produces a well-known distortion of themagnetic map, in which sites of excitation are "smeared" moreextensively in the direction of the electric field. Assuming thatspatial smearing is symmetrical, however, the scalp center of gravity ascalculated here will be unaffected, and should accurately reflect themean position of excitation even in the absence of formal deconvolution.

In comparison to electrocorticography, magnetic mapping of the cerebralcortex has important advantages that go beyond its relative safety andease of uses. One of these, obviously, is the ability to study bothhemispheres of the normal brain. Another is the robustness of motoreffects. Direct electrical stimulation of the cortex in conscioussubjects fails to activate any hand movement in as many as 35%, fails toproduce movement of the face or tongue in up to 83%, and occasionallyfails to identify areas of speech arrest anywhere in the dominanthemisphere. Thus it is often impossible, using electrocorticography, tomake a clear physiological distinction between different corticalregions; there simply are not enough sites of activation in a givensubject. But with appropriate techniques magnetic stimulation willalways activate movement of multiple hand muscles in normal subjects,and has produced speech arrest in all but one of several dozen normalsubjects we have surveyed thus far. The reason for this surprisingadvantage of transcranial magnetic stimulation is unknown, but mayrelate to a consistent electric field vector over a larger volume ofcortex.

Our technique has not yet been validated against the Wada test, and thuscannot necessarily substitute for it at present. However, the usual Wadatest patient who harbors intractable epilepsy and a high incidence ofstructural lesions may have atypical patterns of language organization.The Wada procedure is also complicated by a limited time frame andunpredictable drug effects, so that its results may not extrapolate tothe normal population.

Analysis of magnetic speech arrest supports the current interpretationof language organization as modular, rather than the older concept of asingle output area that controls multiple functions. The robustness andconvenience of magnetic mapping should further facilitate theinvestigation of language function in normal brains, and improve ourunderstanding of recovery in those that have suffered impairment.

Magnetic Brain Stimulation for Treatment of Depression

In accordance with the present invention, the present apparatus can alsobe used for the treatment of depression. It has been found that magnetictranscranial brain stimulation can be an effective treatment in avariety of patients, including those who are psychotically depressed ormedication resistant. Treatment of refractory depression using thepresent device having a core of a magnetic or preferably ferromagneticmaterial is believed to be more effective than use of the devicespreviously disclosed in the art. Although the use of left prefrontalrTMS is preferred based on current understanding, it may be possiblethat other forms of stimulation will be found useful with furtherstudies.

In accordance with the present invention, the location of the right handmotor area and relaxed motor threshold are first identified over theleft hemisphere. (See e.g., Epstein C M, Lah J K, Meador K, Weissman JD, Gaitan L E, Dihenia B, Optimized stimulus parameters for lateralizedsuppression of speech with magnetic brain stimulation, Neurology, 1996;47: 1590-1593, the disclosure of which is fully incorporated herein byreference). During stimulation at a rate of 1 Hz, the magnetic coil ismoved across the left central region and the stimulator output isgradually adjusted to locate the point of lowest-intensity activation,followed by the magnetic threshold at that site. This position is thenlabelled with a permanent marker. Determining motor threshold requiresonly approximately 5-10 minutes at the first treatment session, and lesstime in subsequent sessions because the location has already beenmarked. Location of the marked area is facilitated by the use of centerport 62.

The site of rTMS treatment is measured 5 cm anteriorly from the handmotor area on a parasagittal line. (See e.g., George M S, Wasserman E M,Williams W., et al., Changes in mood and hormone levels after rapid-ratetranscranial magnetic stimulation of the prefrontal cortex, J.Neuropsychiatry Clin. Neurosci. 1996; 8:172-180, the disclosure of whichis fully incorporated herein by reference.) At each rTMS treatment, thestimulator output is set to 110% of relaxed motor threshold and arepetition rate of 10 Hz. Stimulation is delivered in ten trains of 5seconds each, with trains beginning 30 seconds apart. The coil isoriented so that electric fields are induced along a sagittal plane. Earprotection was worn throughout.

During use of the device for treatment, all treatments were administeredonce daily for five (5) consecutive weekdays. Patients lay supine withthe head elevated on a pillow. Continuous cardiac monitoring wasperformed, and blood pressure was taken every 60 seconds duringstimulation. rTMS was performed using a damped cosine pulse and theferromagnetic core stimulator disclosed herein.

Using this magnetic stimulator, left prefrontal rTMS was effected withgood results. The device and method were tested on 32 patients who hadbeen referred for electroconvulsive therapy (ECT). Ten patients hadpreviously received ECT. All patients studied had received at least onesix week trial of an antidepressant at a therapeutic dose (See Table 1of FIG. 5). All of the patients met DSM-IV criteria for a MajorDepressive episode (29 unipolar, 3 bipolar), were rated at leastmoderately ill on the Clinical Global Impression Scale (CGI) and had apre-treatment score on the Hamilton Depression Scale (Ham-D, 21 item)greater than 20. Diagnoses were made by a physician (GSF) using a DSM-IVchecklist during a structured clinical interview.

In general, patients were tapered off psychotropic medications prior tobeginning a course of rTMS, although in our studies, four of thepatients could not be taken off of medications due to the severity oftheir illness. In no case was a patient started on a new psychotropicmedication during rTMS treatment. Patients with a history of recentmyocardial infarction, cardiac pacemaker, intracranial metallic objectsor increased intracranial pressure were excluded. Responders werecharacterized according to the criteria of Sackheim, et al.: they had toshow a 60% reduction from their pre-treatment Ham-D score and apost-rTMS maximum score of 16 points. (See, Sackheim H A, Decina P,Portnoy S, Kanzler M, Kerr B, Malitz S., Effects of electrode placementon the efficacy of titrated low-dosage ECT, Am. J. Psychaitry, 1987;144: 1449-1455, the disclosure of which is fully incorporated herein byreference.) In addition, responders had to be rated as moderately tomarkedly improved on a 7 point CGI. These ratings were completed by thepatient's clinical treatment team along with the physician on the rTMSservice (GSF). All ratings were obtained prior to beginning rTMS andwithin 48 hours after the fifth treatment.

Of those patients studied, 28 out of 32 completed the course of rTMStreatments. Mean Ham-D scores fell from 31 to 15 (p<0.0001). There were16 responders (56%) and 12 non-responders (44%). Fourteen patients (50%)had post-treatment Ham-D scores of less than 10. When the differences inpost-treatment and pre-treatment Ham-D scores were plotted on ahistogram, the non-responders and responders appeared to fall into twodistinct clusters (See FIG. 6). Patients who responded to rTMS did notdiffer with respect to age (p=0.3), sex (p=0.5) or pre-rTMS Ham-D scores(p=0.4) from non-responders (See Table 2 in FIG. 5). Fourteen of the 25(56%) patients with Major Depression (Unipolar, Recurrent) responded totreatment using the present stimulator. One of the 2 patients withPsychotic Depression responded (See Table 3 in FIG. 5). Two of 3patients with Bipolar Disorder responded to rTMS using the presentstimulator (See Table 3 in FIG. 5). Of ten patients who reported afavorable response to ECT in the past, 8 of these responded to rTMSusing the present magnetic stimulator.

Accordingly, the present device and method has been found to be usefulfor treatment of depression as an alternative to the devices and methodspreviously used in the art.

In several patients studied, however, some adverse events were reported.Two patients (a 47 year old male and a 33 year female) requestedtermination after one treatment because of pain over the left frontalregion during stimulation. In both cases, the pain stopped immediately,when stimulation ceased.

A 44 year old female with preexisting motor tics of the right and lowerextremity had recurrence of these movements during the first rTMStreatment. Periodic limb flexion persisted for 20 minutes without changein speech or alertness, and could be quenched repeatedly with gentlepressure to the arm or leg. Movements ceased after 2 mg of lorazepam IV,without any subsequent complications.

A 51 year old hypertensive female developed left arm, leg, and lowerface paresthesias 20 minutes after her first rTMS treatment.Paresthesias remitted completely over several days. Completeneurological examination five hours after onset was normal. MRI and MRAthe next day were normal. This event was assessed as a probable smalllacunar infarction in the right hemisphere.

A 46 year old female, who was a responder to rTMS, initially reportedthat she had no history of epilepsy prior to beginning treatment;however, two weeks after starting treatment she reported apparent leftfocal motor seizures, and admitted preexisting twitching of the leftface. All episodes were remote from the times of rTMS by at leastseveral hours. Complete neurological examination, EEG, and MRI werenormal. Seizures continued and became bilateral despite therapeuticphenytoin levels, and were highly correlated with attendance at churchand funerals. She underwent inpatient video-EEG monitoring, whichconfirmed a diagnosis of psychogenic pseudoseizures.

Ten patients complained of mild headache during treatment. Theseheadaches ended immediately after stimulation stopped; all ten patientscompleted the course of rTMS, and none required treatment withanalgesics. No patients complained of memory or cognitive side effectsduring or after rTMS. rTMS had no effect on blood pressure or heartrate.

Accordingly, the present inventions are believed to be significantimprovements over the prior art, and have application incharacterization, localization and treatment of brain function,including for depression and speech arrest. In addition to thedisclosure of the inventions provided herein, several additionalreferences may be of interest to those of ordinary skill and useful foradditional background and information of relevance. These referencesinclude:

1. Pascual-Leone A, Gates J R, Dhuna A. Induction of speech arrest andcounting errors with rapid-rate transcranial magnetic stimulation.Neurology 1991;41:697-702.

2. Michelucci R, Valzania F, Passarelli D, et al. Rapid-ratetranscranial magnetic stimulation and hemispheric language dominance:usefulness and safety in epilepsy. Neurology 1994;44:1697-1700.

3. Jenum P, Friberg L, Fuglsang-Frederiksen A, Dam M. Speechlocalization using repetitive transcranial magnetic stimulation.Neurology 1994;44:269-273.

4. Pascual-Leone A, Houser C M, Reese K, et al. Safety of rapid-ratetranscranial magnetic stimulation in normal volunteers. ElectroencephClin Neurophysiol 1993;89:120-130.

5. Lesser R P, Luders H, Klem G, et al. Extraoperative corticalfunctional localization in patients with epilepsy. J Clin Neurophysiol1987;4:27-53.

6. Ojemann G A, Sutherling W A, Lesser R P, Dinner D S, Jayakar P, SaintHilaire J-M. Cortical stimulation. In: Engel J, Jr, ed. Surgicaltreatment of the epilepsies. 2nd ed. New York: Raven Press,1993:399-414.

7. Cherlow D G, Dymond A M, Crandall P H, Walter R D, Serafetinides E A.Evoked response and after-discharge thresholds to electrical stimulationin temporal lobe epileptics. Arch Neurol 1977;34:527-531.

8. Epstein C M, Schwartzberg D G, Davey K R, Sudderth D B. Localizingthe site of magnetic brain stimulation in humans. Neurology1990;40:666-670.

9. Wassermann E M, McShane L M, Hallett M, Cohen L G. Noninvasivemapping of muscle representations in human motor cortex. ElectroencephClin Neurophysiol 1992;85:1-8.

10. Sackeim H A, Decina P. Portnoy S. Kanzier M. Kerr B. Malitz S.Effects of electrode placement on the efficacy of titrated low-dosageECT. Am J Psychiatry, 1987; 144:1449-1455

11. Pascual-Leone A, Houser C M, Reeves K, et al. Safety of rapid-ratetranscranial magnetic stimulation in normal volunteers.Electroencephalogr Clin Europhysiol. 1993; 89:120-130.

12. Wasserman E M, Grafman J, Berry C, Hollnagel C, Wild K, Clark K,Hallett M. Use and safety of a new repetitive transcranial magneticstimulator.

13. Huffnagel A, Claus D, Brunhoelzl C, Sudhop T. Short-term memory: noevidence of effect of rapid-repetitive transcranial magnetic stimulationin healthy individuals. J Neurol. 1993;240:373-376.

14. Fleischmann A, Prolov K, Abarbanel J, Belmaker R H. The effect oftranscranial magnetic stimulation of rat brain on behavioral models ofdepression. Brain Research. 1995;699:130-132.

15. Fleischmann A, Steppel J, Leon A, et al. The effect of transcranialmagnetic stimulation compared with electroconvulsive shock on ratapomorphine induced stereotypy. Eur Neuropsychopharmacol.1994;4:449-450.

16. Klein E, Ben-Shachar D, Grisaru N, Belmaker R H. Effects of rTMS onbrain monoamines, receptors and animal models of depression. Presentedto Biological Psychiatry; May, 1997, San Diego, Calif.

17. Epstein, C M, Schwartzberg D G, Davey K R, Sudderth D B, Localizingthe site of magnetic brain stimulation in humans, Neurology 1990;40:666-670.

18. Epstein C M, Lah J J, Meador K, Weissman J D, Gaitain L E, DiheniaB, Optimum stimulus parameters for lateralized suppression of speechwith magnetic brain stimulation, Neurology, 47: 1590-1593 (December1996).

The disclosures of all references cited in the present application areto be considered fully incorporated herein by reference.

Having described this invention with regard to specific embodiments, itis to be understood that the description is not meant as a limitationsince further modifications may suggest themselves to those skilled inthe art and it is intended to cover such modifications as fall withinthe scope of the appended claims.

We claim:
 1. A transcranial magnetic nerve stimulator, comprising:amagnetic core being approximately hemispherical, said magnetic corecomprising a highly saturable magnetic material having a magneticsaturation of at least 0.5 Tesla, and having windings of wire around atleast a portion of said magnetic core.
 2. A transcranial magnetic nervestimulator as claimed in claim 1, wherein said magnetic core is of ashape which approximately conforms to a portion of the surface of ahuman head.
 3. A transcranial magnetic nerve stimulator as claimed inclaim 1, wherein said magnetic stimulator is provided with a portextending through said stimulator.
 4. A transcranial magnetic nervestimulator as claimed in claim 1, wherein said core is made of amaterial which is ferromagnetic.
 5. A transcranial magnetic nervestimulator as claimed in claim 1, wherein said magnetic core iscomprised of a plurality of adjacent cores.
 6. A transcranial magneticnerve stimulator as claimed in claim 1, wherein said magnetic corecomprises four adjacent cores.
 7. A transcranial magnetic nervestimulator as claimed in claim 1, wherein said magnetic core comprises amagnetic material having a magnetic saturation of at least 1.5 Tesla. 8.A transcranial magnetic nerve stimulator as claimed in claim 1, whereinsaid magnetic core comprises a magnetic material having a magneticsaturation of at least 2.0 Tesla.
 9. A transcranial magnetic nervestimulator as claimed in claim 5, wherein at least one of said adjacentcores spans an angle of approximately 208 degrees.
 10. A transcranialmagnetic nerve stimulator as claimed in claim 5, wherein at least one ofsaid adjacent cores spans an angle of approximately 205-215 degrees. 11.A transcranial magnetic nerve stimulator as claimed in claim 5, whereinat least one of said adjacent cores spans an angle of approximately190-230 degrees.
 12. A transcranial magnetic nerve stimulator as claimedin claim 5, wherein at least one of said adjacent cores spans an angleof approximately 180-270 degrees.
 13. A transcranial magnetic nervestimulator as claimed in claim 5, wherein all of said adjacent coresspan an angle of approximately 208 degrees.
 14. A transcranial magneticnerve stimulator as claimed in claim 5, wherein all of said adjacentcores span an angle of approximately 205-215 degrees.
 15. A transcranialmagnetic nerve stimulator as claimed in claim 5, wherein all of saidadjacent cores span an angle of approximately 190-230 degrees.
 16. Atranscranial magnetic nerve stimulator as claimed in claim 5, whereinall of said adjacent cores span an angle of approximately 180-270degrees.
 17. A transcranial magnetic nerve stimulator as claimed inclaim 1, further comprising a power source for providing power to saidstimulator.
 18. A transcranial magnetic nerve stimulator as claimed inclaim 1, wherein said magnetic material comprises vanadium permendur.19. A transcranial magnetic nerve stimulator as claimed in claim 5,wherein at least one of said cores comprise vanadium permendur.
 20. Atranscranial magnetic nerve stimulator as claimed in claim 5, whereinall of said cores comprise vanadium permendur.
 21. A transcranialmagnetic nerve stimulator as claimed in claim 5, wherein at least one ofsaid cores comprise 3% grain oriented steel.
 22. A transcranial magneticnerve stimulator as claimed in claim 5, wherein all of said corescomprise 3% grain oriented steel.
 23. A transcranial magnetic nervestimulator as claimed in claim 5, wherein one of said cores comprises a50% nickel alloy.
 24. A transcranial magnetic nerve stimulator asclaimed in claim 5, wherein at least one of said cores has an an outerdiameter between approximately 2 and 7 inches.
 25. A transcranialmagnetic nerve stimulator as claimed in claim 5, wherein all of saidcores have an outer diameter between approximately 2 and 7 inches.
 26. Atranscranial magnetic nerve stimulator as claimed in claim 5, wherein atleast one of said cores has an inner diameter between approximately 0.2and 1.5 inches.
 27. A transcranial magnetic nerve stimulator as claimedin claim 5, wherein all of said cores have an inner diameter between 0.2and 1.5 inches.
 28. A transcranial magnetic nerve stimulator as claimedin claim 1, wherein said core comprises a semicircular section and twotriangular sections, said semicircular section and said two triangularsections being integrally formed as a single piece.
 29. A transcranialmagnetic nerve stimulator as claimed in claim 1, wherein said corecomprises a semicircular section further having two triangular sectionsattached thereto.
 30. A transcranial magnetic nerve stimulator asclaimed in claim 1, wherein said core is comprised of at least twoseparate magnetic materials.
 31. A transcranial magnetic nervestimulator as claimed in claim 30, wherein one of said materials is a50% nickel alloy.
 32. A transcranial magnetic nerve stimulator asclaimed in claim 30, wherein said materials comprise vanadium permendurand a 50% nickel alloy.
 33. A method for treatment of depression,comprising(a) selecting a patient suffering from a depressive disorder;and, (b) magnetically stimulating the brain of the patienttranscranially using a transcranial magnetic stimulator-having amagnetic core.
 34. A method for treatment of depression as claimed inclaim 33, wherein said stimulator is a stimulator in accordance withclaim
 1. 35. A method for studying the brain, comprising:(a) Directing asubject to perform a predetermined task; and, (b) Magneticallystimulating the brain of said subject transcranially during performanceof said predetermined task using a transcranial magnetic stimulatorhaving a magnetic core; and, (c) Monitoring the speech arrest of saidsubject due to said magnetic stimulation.
 36. A method for treatment ofdepression as claimed in claim 35, wherein said stimulator is astimulator in accordance with claim
 1. 37. A method for treatment ofdepression as claimed in claim 33, wherein said stimulator is astimulator in accordance with claim
 2. 38. A method for treatment ofdepression as claimed in claim 33, wherein said stimulator is astimulator in accordance with claim
 3. 39. A method for treatment ofdepression as claimed in claim 33, wherein said stimulator is astimulator in accordance with claim
 4. 40. A method for treatment ofdepression as claimed in claim 33, wherein said stimulator is astimulator in accordance with claim
 5. 41. A method for treatment ofdepression as claimed in claim 33, wherein said stimulator is astimulator in accordance with claim
 6. 42. A method for treatment ofdepression as claimed in claim 33, wherein said stimulator is astimulator in accordance with claim
 7. 43. A method for treatment ofdepression as claimed in claim 33, wherein said stimulator is astimulator in accordance with claim
 7. 44. A method for treatment ofdepression as claimed in claim 33, wherein said stimulator is astimulator in accordance with claim
 8. 45. A method for treatment ofdepression as claimed in claim 33, wherein said stimulator comprises amagnetic core spanning an angle of approximately 208 degrees.
 46. Amethod for treatment of depression as claimed in claim 33, wherein saidstimulator comprises a magnetic core spanning an angle of approximately205-215 degrees.
 47. A method for treatment of depression as claimed inclaim 33, wherein said stimulator comprises a magnetic core spanning anangle of approximately 190-230 degrees.
 48. A method for treatment ofdepression as claimed in claim 33, wherein said stimulator comprises amagnetic core spanning an angle of approximately 180-270 degrees.
 49. Amethod for treatment of depression as claimed in claim 33, wherein saidstimulator is a stimulator in accordance with claim
 18. 50. A method fortreatment of depression as claimed in claim 33, wherein said stimulatoris a stimulator in accordance with claim
 21. 51. A method for treatmentof depression as claimed in claim 33, wherein said stimulator is astimulator in accordance with claim
 22. 52. A method for treatment ofdepression as claimed in claim 33, wherein said stimulator is astimulator in accordance with claim 30.